Journal Article

Cell activation via CD44 occurs in advanced stages of squamous cell carcinogenesis

Silvia Bruno, Marina Fabbi, Micaela Tiso, Barbara Santamaria, Fabio Ghiotto, Daniele Saverino, Claudya Tenca, Daniela Zarcone, Silvano Ferrini, Ermanno Ciccone and Carlo E. Grossi

in Carcinogenesis

Volume 21, issue 5, pages 893-900
Published in print May 2000 | ISSN: 0143-3334
Published online May 2000 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/21.5.893
Cell activation via CD44 occurs in advanced stages of squamous cell carcinogenesis

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Squamous cell carcinoma (SCC) derives from dysplastic or metaplastic stratified epithelia. The process of squamous cell carcinogenesis has been investigated for the potential role of the adhesion molecule CD44, whose standard form (CD44s) and isoforms generated by alternative splicing of variant exons are known to display altered expression during tumorigenesis in other systems. We have utilized an in vitro correlate of squamous cell carcinogenesis, in which progression stages from normal squamous epithelium to dysplastic lesions and to SCC are represented by primary cultures of normal keratinocytes, by human papilloma virus-immortalized keratinocytes (UP) and by HPVimmortalized/v-Ha-ras transfected tumorigenic keratinocytes (UPR). We investigated expression of CD44 and of variant isoforms, from mRNA to intracellular and surface protein levels, and found no relationship between expression of CD44 and stages of squamous cell carcinogenesis. However, when the function of CD44 was analyzed as Ca2+ mobilization ability upon monoclonal antibody binding and crosslinking, signal transduction via CD44 was found only for the neoplastic stage (UPR cells). Ca2+ mobilization was completely independent of density of surface CD44. We have performed similar analyses in an in vitro model of SCC in which four squamous tumor cell lines and UPR cells were sorted according to increasing resistance to external cytotoxic stimuli, i.e. starving conditions, treatment with the retinoid N-(4-hydroxyphenyl)retinamide and cytolytic activity of effector lymphokine-activated killer cells. No relationship between expression of CD44 and level of cell resistance against external cell death-inducing stimuli was found, while CD44-mediated Ca2+ mobilization ability was restricted to the highly resistant tumor cell lines. Our results indicate that the role(s) of CD44 in squamous cell proliferative disorders can be evinced from the functional features of the molecule, rather than from its phenotypic repertoire.

Keywords: CD44s, standard form of CD44; CD44V, variant isoform of CD44; ECM, extracellular matrix; EGF, epidermal growth factor; FCS, fetal calf serum; HA, hyaluronic acid; 4-HPR, N-(4-hydroxyphenyl)retinamide; HPV, human papilloma virus; LAK cells, lymphokine-activated killer cells; mAb, monoclonal antibody; PBL, peripheral blood lymphocytes; PBS, phosphate-buffered saline; PI, propidium iodide; SCC, squamous cell carcinoma.

Journal Article.  6775 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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